title: Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation.
abstract: Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.
authors.affiliation: Department of Anesthesia, Harvard Medical School, Boston, MA, USA.
authors.forename: Andrea U
authors.initials: AU
authors.lastname: Steinbicker
authors.forename: Chetana
authors.initials: C
authors.lastname: Sachidanandan
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Vonner
authors.forename: Rushdia Z
authors.initials: RZ
authors.lastname: Yusuf
authors.forename: Donna Y
authors.initials: DY
authors.lastname: Deng
authors.forename: Carol S
authors.initials: CS
authors.lastname: Lai
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Rauwerdink
authors.forename: Julia C
authors.initials: JC
authors.lastname: Winn
authors.forename: Borja
authors.initials: B
authors.lastname: Saez
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Cook
authors.forename: Brian A
authors.initials: BA
authors.lastname: Szekely
authors.forename: Cindy N
authors.initials: CN
authors.lastname: Roy
authors.forename: Jasbir S
authors.initials: JS
authors.lastname: Seehra
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
mesh_terms: D000740:Anemia / Q000209:etiology* / Q000517:prevention & control*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D056945:Hep G2 Cells; D064451:Hepcidins; D006801:Humans; D007249:Inflammation / Q000150:complications*; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014425:Turpentine / Q000633:toxicity; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D023181:Antimicrobial Cationic Peptides; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D064451:Hepcidins; D015850:Interleukin-6; D011720:Pyrazoles; D011743:Pyrimidines; D011994:Recombinant Proteins; D014425:Turpentine; D029961:Zebrafish Proteins; D000099176:Noggin Protein; C578702:HAMP protein, human; C579599:Hamp protein, mouse; C508600:IL6 protein, human; C554430:LDN 193189